Bioactive porous bone graft implants

ABSTRACT

Bioactive porous bone graft implants in various forms suitable for bone tissue regeneration and/or repair, as well as methods of use, are provided. The implants are formed of bioactive glass and have an engineered porosity. The implants may take the form of a putty, foam, fibrous cluster, fibrous matrix, granular matrix, or combinations thereof and allow for enhanced clinical results as well as ease of handling.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.14/536,228, filed Nov. 7, 2014, now U.S. Patent No. 10,335,516, which isa divisional of U.S. patent application Ser. No. 13/830,629, filed Mar.14, 2013, now U.S. Pat. No. 8,883,195, the entire contents of which areherein incorporated by reference.

FIELD

The present disclosure relates generally to bone graft materials andmethods of using such materials as implants for bone tissue regrowth.More particularly, the present disclosure relates to bioactive porousbone graft implants in various forms suitable for use in bone tissueregeneration and/or repair, as well as methods of use.

BACKGROUND

The role of bone graft materials in clinical applications to aid thehealing of bone has been well documented over the years. Most bone graftmaterials that are currently available, however, have failed to deliverthe anticipated results necessary to make these materials a routinetherapeutic application in reconstructive surgery. Improved bone graftmaterials for forming bone tissue implants that can produce reliable andconsistent results are therefore still needed and desired.

In recent years intensive studies have been made on bone graft materialsin the hopes of identifying the key features necessary to produce anideal bone graft implant, as well as to proffer a theory of themechanism of action that results in successful bone tissue growth. Atleast one recent study has suggested that a successful bone tissuescaffold should consider the physicochemical properties, morphology anddegradation kinetics of the bone being treated. (“Bone tissueengineering: from bench to bedside”, Woodruff et al., Materials Today,15(10): 430-435 (2012)). According to the study, porosity is necessaryto allow vascularization, and the desired scaffold should have a porousinterconnected pore network with surface properties that are optimizedfor cell attachment, migration, proliferation and differentiation. Atthe same time, the scaffold should be biocompatible and allow flowtransport of nutrients and metabolic waste. Just as important is thescaffold's ability to provide a controllable rate of biodegradation tocompliment cell and/or tissue growth and maturation. Finally, theability to model and/or customize the external size and shape of thescaffold to allow a customized fit for the individual patient is ofequal importance.

Woodruff, et. al. also suggested that the rate of degradation of thescaffold must be compatible with the rate of bone tissue formation,remodeling and maturation. Recent studies have demonstrated that initialbone tissue ingrowth does not equate to tissue maturation andremodeling. According to the study, most of the currently available bonegraft implants are formulated to degrade as soon as new tissue emerges,and at a faster rate than the new bone tissue is able to mature,resulting in less than desirable clinical outcomes.

Other researchers have emphasized different aspects as the core featuresof an ideal bone graft implant. For example, many believe that theimplant's ability to provide adequate structural support or mechanicalintegrity for new cellular activity is the main factor to achievingclinical success, while others emphasize the role of porosity as the keyfeature. The roles of porosity, pore size and pore size distribution inpromoting revascularization, healing, and remodeling of bone have longbeen recognized as important contributing factors for successful bonegrafting implants. Many studies have suggested an ideal range ofporosities and pore size distributions for achieving bone graft success.However, as clinical results have shown, a biocompatible bone grafthaving the correct structure and mechanical integrity for new bonegrowth or having the requisite porosities and pore distributions alonedoes not guarantee a good clinical outcome. What is clear from thiscollective body of research is that the ideal bone graft implant shouldpossess a combination of structural and functional features that act insynergy to allow the bone graft implant to support the biologicalactivity and an effective mechanism of action as time progresses.

Currently available bone graft implants fall short of meeting theserequirements. That is, many bone graft implants tend to suffer from oneor more of the problems previously mentioned, while others may havedifferent, negatively associated complications or shortcomings. Oneexample of such a graft implant is autograft implants. Autograftimplants have acceptable physical and biological properties and exhibitthe appropriate mechanical structure and integrity for bone growth.However, the use of autogenous bone requires the patient to undergomultiple or extended surgeries, consequently increasing the time thepatient is under anesthesia, and leading to considerable pain, increasedrisk of infection and other complications, and morbidity at the donorsite.

When it comes to synthetic bone graft substitutes, the most rapidlyexpanding category consists of products based on calcium sulfate,hydroxyapatite and tricalcium phosphate. Whether in the form ofinjectable cements, blocks or morsels, these materials have a proventrack record of being effective, safe bone graft substitutes forselected clinical applications. Recently, new materials such asbioactive glass (“BAG”) have become an increasingly viable alternativeor supplement to natural bone-derived graft materials. In comparison toautograft implants, these new synthetic implants have the advantage ofavoiding painful and inherently risky harvesting procedures on patients.Also, the use of these synthetic, non-bone derived materials can reducethe risk of disease transmission. Like autograft and allograft implants,these new artificial implants can serve as osteoconductive scaffoldsthat promote bone regrowth. Preferably, the graft implant is resorbableand is eventually replaced with new bone tissue.

Many artificial bone grafts available today comprise materials that haveproperties similar to natural bone, such as implants containing calciumphosphates. Exemplary calcium phosphate implants contain type-Bcarbonated hydroxyapatite whose composition in general may be describedas (Ca₅(PO₄)_(3x)(CO₃)_(x)(OH)). Calcium phosphate ceramics have beenfabricated and implanted in mammals in various forms including, but notlimited to, shaped bodies and cements. Different stoichiometricimplants, such as hydroxyapatite (HA), tricalcium phosphate (TCP),tetracalcium phosphate (TTCP), and other calcium phosphate (CaP) saltsand minerals have all been employed in attempts to match theadaptability, biocompatibility, structure, and strength of natural bone.Although calcium phosphate based materials are widely accepted, theylack the ease of handling, flexibility and capacity to serve as a liquidcarrier/storage media necessary to be used in a wide array of clinicalapplications. Calcium phosphate materials are inherently rigid, and tofacilitate handling are generally provided as part of an admixture witha carrier material; such admixtures typically have an active calciumphosphate ingredient to carrier volume ratio of about 50:50, and mayhave a ratio as low as 10:90.

As previously mentioned, the roles of porosity, pore size and pore sizedistribution in promoting revascularization, healing, and remodeling ofbone have been recognized as important contributing factors forsuccessful bone grafting . Yet currently available bone graft implantsstill lack the requisite chemical and physical properties necessary foran ideal graft implant. For instance, currently available graft implantstend to resorb too quickly (e.g., within a few weeks), while some taketoo long (e.g., over years) to resorb due to the implant's chemicalcomposition and structure. For example, certain implants made fromhydroxyapatite tend to take too long to resorb, while implants made fromcalcium sulfate or β-TCP tend to resorb too quickly. Further, if theporosity of the implant is too high (e.g., around 90%), there may not beenough base material left after resorption has taken place to supportosteoconduction. Conversely, if the porosity of the implant is too low(e.g., 10%), then too much material must be resorbed, leading to longerresorption rates. In addition, the excess material means there may notbe enough room left in the residual graft implant for cell infiltration.Other times, the graft implants may be too soft, such that any kind ofphysical pressure exerted on them during clinical usage causes them tolose the fluids retained by them.

Accordingly, there continues to be a need for better bone graftimplants. For instance, it would be desirable to provide improved bonegraft implants offering the benefits just described, and in a form thatis even easier to handle and allows even better clinical results.Embodiments of the present disclosure address these and other needs.

SUMMARY

The present disclosure provides bone graft materials and implants formedfrom these materials that are engineered with a combination ofstructural and functional features that act in synergy to allow the bonegraft implant to support cell proliferation and new tissue growth overtime. The implants serve as cellular scaffolds to provide the necessaryporosity and pore size distribution to allow proper vascularization,optimized cell attachment, migration, proliferation, anddifferentiation. The implants are formed of synthetic materials that arebiocompatible and offer the requisite mechanical integrity to supportcontinued cell proliferation throughout the healing process. Inaddition, the materials are formulated for improved clinical handlingand allow easy modeling and/or customization of the external size andshape to produce a customized implant for the anatomic site.

In one embodiment, a porous, composite bone graft implant is provided.The implant may comprise a first component comprising a bioactive glassand a second component comprising a bioactive material. Each of thecomponents may have a different resorption capacity than the othercomponent. The implant may further comprise a pore size distributionincluding pores characterized by pore diameters ranging from about 100nanometers to about 1 millimeter. The bioactive glass may comprisebioactive glass fibers, bioactive glass granules, or combinationsthereof. The second component may comprise a bioactive glass orglass-ceramic material.

In another embodiment, a porous, composite bone graft implant isprovided. The implant may comprise a first component comprisingbioactive glass fibers and a second component comprising a bioactiveglass or glass-ceramic material. Each of the components may have adifferent resorption capacity than the other component. The implant mayfurther comprise a pore size distribution including pores characterizedby pore diameters ranging from about 100 nanometers to about 1millimeter. The implant may further include bioactive glass granules.The second component may comprise a coating surrounding each of thebioactive glass fibers of the first component. The second component mayalso comprise a coating surrounding the fibrous first component.

In still another embodiment, a porous, composite bone graft implant isprovided. The implant may comprise a first component comprisingbioactive glass granules and a second component comprising a bioactiveglass or glass-ceramic material. Each of the components may have adifferent resorption capacity than the other component. The implant mayfurther comprise a pore size distribution including pores characterizedby pore diameters ranging from about 100 nanometers to about 1millimeter. The implant may further comprise bioactive glass fibers. Thesecond component may comprise a coating surrounding each of thebioactive glass granules of the first component. The second componentmay also comprise a coating surrounding the plurality of granules of thefirst component.

In even still another embodiment, a composite bone graft implant isprovided. The implant may comprise a bioactive glass material, and acarrier material. The implant may comprise a pore size distributionincluding pores characterized by pore diameters ranging from 100nanometers to about 1 millimeter. The bioactive glass may comprisebioactive glass fibers, bioactive glass granules, or combinationsthereof. The implant may comprise a putty or a foam.

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory onlyand are not restrictive of the disclosure. Additional features of thedisclosure will be set forth in part in the description which follows ormay be learned by practice of the disclosure.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are incorporated in and constitute apart of this specification, illustrate several embodiments of thedisclosure and together with the description, serve to explain theprinciples of the disclosure.

FIG. 1A illustrates a perspective view of an exemplary embodiment of abone graft implant of the present disclosure in which the implantcomprises two different fibrous materials.

FIG. 1B is an enlarged view of a portion of the implant of FIG. 1A.

FIG. 1C illustrates a partial view of another exemplary embodiment of abone graft implant of the present disclosure in which the implantcomprises two different fibrous materials having different diameters.

FIG. 2 illustrates a partial view of still another exemplary embodimentof a bone graft implant of the present disclosure in which the implantcomprises fibers that are fused.

FIG. 3 illustrates a cross-sectional view of an individual bioactivefiber coated in a bioactive material.

FIG. 4 illustrates a cross-sectional view of an individual bioactivefiber having a fused coating of a bioactive material.

FIG. 5A illustrates a partial cutaway view of an exemplary embodiment ofa bone graft implant of the present disclosure in which the implantcomprises a fibrous matrix encased in a bioactive shell.

FIG. 5B illustrates a partial cutaway view of still another exemplaryembodiment of a bone graft implant of the present disclosure in whichthe implant comprises a fibrous matrix encased in a hardened bioactiveshell.

FIG. 5C illustrates a partial view of yet still another exemplaryembodiment of a bone graft implant of the present disclosure in whichthe implant comprises a hardened fibrous matrix encased in a hardenedbioactive shell.

FIG. 6A illustrates a partial view of an exemplary embodiment of a bonegraft implant of the present disclosure in which the implant comprises afibrous matrix combined with fibrous clusters.

FIG. 6B illustrates a partial view of another exemplary embodiment of abone graft implant of the present disclosure in which the implantcomprises a fibrous matrix combined with granules.

FIG. 6C illustrates a partial cutaway view of an exemplary embodiment ofa bone graft implant of the present disclosure in which the coatedimplant comprises a fibrous matrix combined with coated granules.

FIG. 7A illustrates a partial cutaway view of an exemplary embodiment ofa bone graft implant of the present disclosure comprising a fibrouscluster.

FIG. 7B illustrates a partial cutaway view of an exemplary embodiment ofa bone graft implant of the present disclosure comprising a fusedfibrous cluster.

FIG. 7C illustrates a partial cutaway view of an exemplary embodiment ofa bone graft implant of the present disclosure comprising a sinteredporous granule.

FIG. 8 illustrates a partial cutaway view of an exemplary embodiment ofa bone graft implant of the present disclosure comprising a fibrousmatrix with granules and a porous coating.

FIG. 9 illustrates a cross-sectional view of an exemplary embodiment ofa bone graft implant of the present disclosure comprising a fibrousmatrix with a granule layer and outer coating.

FIG. 10 illustrates a perspective view of another exemplary embodimentof a bone graft implant of the present disclosure in which the implantcomprises fibrous clusters and granules.

FIG. 11 illustrates a partial view of another exemplary embodiment of abone graft implant of the present disclosure in which the implantcomprises a fibrous matrix combined with fibrous clusters.

FIG. 12 illustrates a perspective view of another exemplary embodimentof a bone graft implant of the present disclosure in which the implantcomprises a fibrous matrix with fibrous clusters and granules.

FIG. 13 shows a scanning electron micrograph (SEM) of a fibrousbioactive glass implant of the present disclosure.

FIG. 14 shows a scanning electron micrograph (SEM) of a bioactive glassimplant of the present disclosure comprising a fibrous matrix withgranules.

FIG. 15 shows a scanning electron micrograph (SEM) of a fibrous clusterof the present disclosure.

FIG. 16 shows a scanning electron micrograph (SEM) of the fibrous matrixwithin the cluster of FIG. 15.

The foregoing and other features of the present disclosure will becomeapparent to one skilled in the art to which the present disclosurerelates upon consideration of the following description of exemplaryembodiments with reference to the accompanying drawings.

DETAILED DESCRIPTION OF THE EMBODIMENTS

The present disclosure provides bone graft materials and implants formedfrom these materials that are engineered with a combination ofstructural and functional features that act in synergy to allow the bonegraft implant to support cell proliferation and new tissue growth overtime. The implants provide the necessary porosity and pore sizedistribution to allow proper vascularization, optimized cell attachment,migration, proliferation, and differentiation. The implants are formedof synthetic materials that are biocompatible and offer the requisitemechanical integrity to support continued cell proliferation throughoutthe healing process. In addition, the materials are formulated forimproved handling and allow easy modeling and/or customization of theexternal size and shape of the implants to produce a customized implantfor the anatomic site.

The bone graft implants may be formed of a synthetic material that isboth biocompatible and bioabsorbable or bioresorbable. In addition, thesynthetic material may be bioactive. In one embodiment, the material maybe a material that is bioactive and forms a calcium phosphate layer onits surface upon implantation. In another embodiment, the material maycomprise a bioactive glass (“BAG”). Suitable bioactive glasses includesol gel derived bioactive glass, melt derived bioactive glass, silicabased bioactive glass, silica free bioactive glass such as borate basedbioactive glass and phosphate based bioactive glass, crystallizedbioactive glass (either partially or wholly), and bioactive glasscontaining trace elements or metals such as copper, zinc, strontium,magnesium, zinc, fluoride, mineralogical calcium sources, and the like.Examples of sol gel derived bioactive glass include S70C30 characterizedby the general implant of 70 mol % SiO₂, 30 mol % CaO. Examples of meltderived bioactive glass include 45S5 characterized by the generalimplant of 46.1 mol % SiO₂, 26.9 mol % CaO, 24.4 mol % Na₂O and 2.5 mol% P₂O₅, S53P4, and 58S characterized by the general implant of 60 mol %SiO₂, 36 mol % CaO and 4 mol % P₂O₅. Another suitable bioactive glassmay also be 13-93 bioactive glass.

The bioactive glass forms the base material from which the engineeredbone graft implants of the present disclosure are composed. Thebioactive glass may take the form of fibers, granules, or a combinationof both. By the term granules, what is meant is at least one fragment ormore of material having a non-rod shaped form, such as a rounded,spherical, globular, or irregular body.

The bioactive glass may be provided in a materially pure form.Additionally, the bioactive glass may be mixed with a carrier for betterclinical handling, such as to make a putty or foam implant. A pliableimplant in the form of a putty may be provided by mixing the bioactiveglass with a flowable or viscous carrier. A foam implant may be providedby embedding the bioactive glass in a porous matrix such as collagen(either human or animal derived) or porous polymer matrix. One of theadvantages of a foam implant is that the porous carrier can also act asa site for attaching cells and growth factors, and may lead to a bettermanaged healing.

The carrier material may be porous and may help contribute to healing.For example, the carrier material may have the appropriate porosity tocreate a capillary effect to bring in cells and/or nutrients to theimplantation site. The carrier material may also possess the chemistryto create osmotic or swelling pressure to bring in nutrients to the siteand resorb quickly in the process. For instance, the carrier materialmay be a polyethylene glycol (PEG) which has a high affinity to water.

The bioactive glass may be manufactured by electrospinning, or by laserspinning for uniformity. For example, where the material is desired in afibrous form, laser spinning would produce fibers of uniform diameters.Further, the bioactive glass fibers may be formed having varyingdiameters and/or cross-sectional shapes, and may even be drawn as hollowtubes. Additionally, the fibers may be meshed, woven, intertangled andthe like for provision into a wide variety of shapes.

The bone graft material may be engineered with fibers having varyingresorption rates. The resorption rate of a fiber is determined orcontrolled by its material composition and by its diameter. The materialcomposition may result in a slow reacting vs. faster reacting product.Similarly, smaller diameter fibers can resorb faster than largerdiameter fibers of the same implant. Also, the overall porosity of thematerial can affect resorption rate. Materials possessing a higherporosity mean there is less material for cells to remove. Conversely,materials possessing a lower porosity mean cells have to do more work,and resorption is slower. Accordingly, the bone graft implants maycontain fibers that have the appropriate material composition as well asdiameter for optimal performance. A combination of different fibers maybe included in the implant in order to achieve the desired result.

Equally as important as the material composition and diameter is thepore size distribution of the open porosity and in particular thesurface area of the open porosity. The present bone graft implantsprovide not only an improved pore size distribution over other bonegraft implants, but a higher surface area for the open pores. The largersurface area of the open porosity of the present implants drives fasterresorption by body fluids, allowing the fluid better access to thepores.

Similar to the bioactive glass fibers, the inclusion of bioactive glassgranules can be accomplished using granules having a wide range of sizesor configurations to include roughened surfaces, very large surfaceareas, and the like. For example, granules may be tailored to includeinterior lumens with perforations to permit exposure of the surface ofthe granule interior. Such granules would be more quickly absorbed,allowing a tailored implant characterized by differential resorbability.The perforated or porous granules could be characterized by uniformdiameters or uniform perforation sizes, for example. The porosityprovided by the granules may be viewed as a secondary range of porosityaccorded the bone graft material or the implant formed from the bonegraft material. By varying the size, transverse diameter, surfacetexture, and configurations of the bioactive glass fibers and granules,if included, the manufacturer has the ability to provide a bioactiveglass bone graft implant with selectively variable characteristics thatcan greatly affect the function of the implant before and after it isimplanted in a patient. The nano and micro sized pores provide superbfluid soak and hold capacity, which enhances the bioactivity andaccordingly the repair process.

Due to the pliability of this fibrous graft material, these samebioactive glass fibers may be formed or shaped into fibrous clusterswith relative ease. These clusters can be achieved with a littlemechanical agitation of the bioactive glass fibrous material. Theresultant fibrous clusters are extremely porous and can easily wick upfluids or other nutrients. Hence, by providing the bioactive glassmaterial in the form of a porous, fibrous cluster, even greater clinicalresults and better handling can be achieved.

The formed and shaped bioactive glass materials of the presentdisclosure, either with or without sintering, share similar attributeswith a finite density material that has been dictated by its processingand the fiber dimensions of the base material (e.g., diameter and lengthof the fibers) that resulted in the cluster formation. The ultra-porousclusters can possess nano, micro, meso, and macro porosity in a gradientthroughout the cluster. Without limitation, a nanopore is intended torepresent a pore having a diameter below about 1 micron and as small as100 nanometers or smaller, a micropore is intended to represent a porehaving a diameter between about 1 to 10 microns, a mesopore is intendedto represent a pore having a diameter between about 10 to 100 microns,and a macropore is intended to represent a pore having a diametergreater than about 100 microns and as large as 1 mm or even larger.Under a consistent manufacturing process, the formed clusters ofbioactive glass can be used with volumetric dosage to fill a bonedefect. Any number of differently sized clusters can be provided forvarious clinical applications.

One of the benefits of providing an ultra-porous bioactive glassmaterial in cluster form is that handling of the material can beimproved. In one manner of handling the cluster of materials, theclusters may be packaged in a syringe with a carrier, and injected intothe bone defect with ease. Another benefit is the additional structuraleffect of having a plurality of clusters of fibers closely packedtogether, forming additional macrostructures to the overall scaffold ofmaterial. Like a sieve, the openings between individual clusters can bebeneficial such as when a filter is desired for various nutrients inblood or bone marrow to concentrate certain desired nutrients at theimplant location.

Of course, it is understood that, while the term cluster is used todescribe the shape of the materials, such term is not intended to limitthe invention to spherical shapes. In fact, the formed cluster shape maycomprise any rounded or irregular shape, so long as it is not a rodshape. In the present disclosure, the term fibrous cluster represents amatrix of randomly oriented fibers of a range of sizes and lengths.Additional granules or particulates of material may be placed randomlyinside this matrix to provide additional advantages. A variety ofmaterials and structure can optionally be employed to control the rateof resoprtion, osteostimulation, osteogenesis, compression resistance,radiopacity, antimicrobial activity, rate of drug elution, and provideoptimal clinical handling for a particular application.

The use of fused or hardened fiber clusters may be advantageous in someinstances, because the fusing provides relative hardness to theclusters, thereby rendering the hardened clusters mechanically stronger.Their combination with the glass granules further enhances thestructural integrity, mechanical strength, and durability of theimplant. Because larger sized granules or clusters will tend to havelonger resorption time, in previous cases the user had to sacrificestrength for speed. However, it is possible to provide larger sizedgranules or clusters to achieve mechanical strength, withoutsignificantly sacrificing the speed of resorption. To this end,ultra-porous clusters can be utilized as just described for fiber-basedand glass-based clusters. Rather than using solid spheres or balls, thepresent disclosure provides ultra-porous clusters that have theintegrity that overall larger sized clusters provide, along with theporosity that allows for speed in resorption. These ultra-porousclusters will tend to absorb more nutrients, resorb quicker, and lead tomuch faster healing and remodeling of the defect.

In some embodiments, the fiber clusters may be partially or fully fusedor hardened to provide hard clusters. Of course, it is contemplated thata combination of both fused fiber clusters (hard clusters) and unfusedor loose fiber clusters (soft clusters) may be used in one applicationsimultaneously. Likewise, combinations of putty, foam, clusters andother formulations of the fibrous graft material may be used in a singleapplication to create an even more sophisticated porosity gradient andultimately offer a better healing response. In some cases, solid porousgranules of the bioactive glass material may also be incorporated intothe implant.

As previously discussed, the ideal bone graft implant must possess acombination of features that act in synergy to allow the bone graftmaterial to support the biological activity of tissue growth andmechanism of action as time progresses. It is known that porosities andpore size distribution play a critical role in the clinical success ofbone graft materials. More specifically, the bone graft implant needs toinclude an appropriate pore size distribution to provide optimized cellattachment, migration, proliferation and differentiation, and to allowflow transport of nutrients and metabolic waste. In addition, in aporous structure the amount and size of the pores, which collectivelyform the pore size gradient, will be directly related to the mechanicalintegrity of the material as well as affect its resorption rate. Havinga stratified porosity gradient will provide a more complex resorptionprofile for the bone graft material, and engineering the material with asuitable pore size gradient will avoid a resorption rate that is toofast or too slow.

As applicants have discovered, this desired pore size distributionincludes a range of porosities that includes macro, meso, micro and nanopores. As previously mentioned, without limitation, a nanopore isintended to represent a pore having a diameter below about 1 micron andas small as 100 nanometers or smaller, a micropore is intended torepresent a pore having a diameter between about 1 to 10 microns, amesopore is intended to represent a pore having a diameter between about10 to 100 microns, and a macropore is intended to represent a porehaving a diameter greater than about 100 microns and as large as 1 mm oreven larger. Accordingly, the bioactive glass material may be providedwith variable degrees of porosity, and is preferably ultraporous. In oneembodiment, the material may have a range of porosities including macro,meso, micro and nano pores. The resultant engineered implant may alsoinclude the same range of porosities, which could be provided as aporous network of matrices within the fibrous scaffold and around thematerial. Accordingly, porosity may be provided inherently by the actualbioactive glass material itself, as well as the matrices separating thematerial within the overall implant.

Another feature of the engineered bone graft implants of the presentdisclosure is their ability to provide mechanical integrity to supportnew tissue growth. Not only should the implant provide the appropriatebiocompatibility and resorption rate, but the surface area should bemaximized to fully support cell proliferation. The engineered implantcan be selectively composed and structured to have differential orstaged resorption capacity, while still being easily molded or shapedinto clinically relevant shapes as needed for different surgical andanatomical applications. Additionally, these engineered implants mayhave differential bioresorbability, compression resistance andradiopacity, and can also maximize the content of active ingredientrelative to carrier materials such as for example collagen.

The present disclosure provides improved bone graft materials and bonegraft implants formed from these materials that are able to sustaintissue growth throughout the healing process. One of the deficiencies ofcurrently available bone graft implants is their lack of ability toprovide proper mechanical scaffolding while supporting cellproliferation over time. The engineered materials and implants of thepresent disclosure overcome this problem by providing, among otherthings, an appropriate combination of porosities (i.e., pore sizedistribution) and high surface area within a porous bioactive glassinfrastructure that serves as an ideal scaffold for tissue growth. Moreimportantly, the range of porosities is distributed throughout theporous bioactive glass infrastructure, which is able to supportcontinued cell proliferation throughout the healing process.

Initially upon implantation, the engineered implants provide a networkof macro, meso, micro and nano pores distributed within a fibrousbioactive glass matrix. These pores can be interconnected, allowing cellmigration throughout the matrix. As surface area is inverselyproportional to the diameter of the pore, the engineered implantsmaximize surface area for cell attachment by providing a desiredsurface-to-volume ratio of nano sized pores. The laws of physics suggestthat these smaller pores are optimal for vascularization. Due to theosmotic pressure of the environment, a capillary effect will be observedwith the nano and micro sized pores that results in biological fluidbeing wicked towards the center of the bioactive glass matrix. Likewise,the larger pores like the macro sized pores are optimal for oxygenationand nutrient exchange within the matrix.

After implantation, a calcium phosphate (CaP) layer forms around theconstruct. This calcium phosphate layer results from the chemicalinteraction of the bioactive glass material and the surroundingbiological environment. At the same time, the smaller sized pores likethe nano sized pores will be resorbing at a rate faster than the rest ofthe implant. As these nano sized pores resorb or become replaced withcells, they will bring in cellular activity and create athree-dimensional biostructure that, within itself, also has its ownporosity. Thus, over time, new cells replace the resorbed material at arate that maintains the mechanical integrity of the new construct. Thenew cells form their own network around the fibrous bioactive glassmatrix, which fibers provide connectivity for the tissue growth. Moreimportantly, because of the widespread distribution of nanoporesthroughout the fibrous matrix, the new cells are present in a densitythat makes the implant mechanically sound.

Unlike traditional bone graft scaffolds, the present bone graft implantsoffer both the necessary structure and function for clinical success,and allow the process of cell proliferation to occur in a non-uniform,multi-faceted fashion with the appropriate balanced rate of new cellproliferation replacing resorbed graft material. More importantly, thisreplacement occurs at select locations within the construct, withoutcompromising overall mechanical integrity. In addition, the materialsand implants allow this new tissue growth process to occur throughoutthe healing process, not just at the beginning of the process. Theconstant and simultaneous activities of cell proliferation andresorption occur throughout the entire healing time with the presentbone graft materials and implants.

In some embodiments, the underlying bioactive material forming thefoundation of the implant may be a bioactive glass. The bioactive glassmay take the form of fibers, making them easy to handle in a clinicalsetting. Accordingly, in one embodiment, the engineered implant may be afibrous scaffold formed of fibrous bioactive glass fibers. These fibersmay be unrestricted, and allowed to move freely over one another.Alternatively, the fibers may be partially or fully fused to provide amore organized, rigid and structured network of fibers. Such a fibrousscaffold would allow for stimulation and induction of the naturalbiologic healing process found in fibrin clots whose mechanism issimilar to that of new bone formation. One theory of the mechanism ofaction as provided by the fibrous nature of the scaffold is providedbelow.

The standard method for healing natural tissue with synthetic materialshas been to provide a device having the microstructure andmacrostructure of the desired end product. Where the desired end productis cancellous bone, traditional bone grafts have been engineered tomimic the architecture of cancellous bone. Although this has been thecurrent standard for bone grafts, it does not take into account the factthat bone is a living tissue. Each bony trabeculae is constantlyundergoing active biologic remodeling in response to load, stress and/ordamage. In addition, cancellous and cortical bone can support a vastnetwork of vasculature. This network not only delivers nutrients tosustain the living environment surrounding bone, but also supports redblood cells and marrow required for basic biologic function. Therefore,merely providing a synthetic material with the same architecture that isnon-biologic is insufficient for optimal bone healing and bone health.Instead, what is required is a mechanism that can recreate the livingstructure of bone.

Traditional synthetics act as a cast, or template, for normal bonetissue to organize and form. Since these synthetics are not naturallyoccurring, eventually the casts or templates have to be resorbed toallow for normal bone to be developed. If these architectured syntheticsdo not resorb and do not allow proper bone healing, they simply becomeforeign bodies that are not only obstacles, but potentially detrimental,to bone healing. This phenomenon has been observed in many studies withslow resorbing or non-resorbing synthetics. Since these synthetics arejust chemically inert, non-biologic structures that only resemble bone,they behave as a mechanical block to normal bone healing anddevelopment.

With the understanding that bone is a living biologic tissue and thatinert structures will only impede bone healing, a different physiologicapproach is presented with the present invention. Healing is a phasicprocess starting with some initial reaction. Each phase builds on thereaction that occurred in the prior phase. Only after a cascade ofphases does the final development of the end product occur—new bonetissue. The traditional method has been to replace or somehow stimulatehealing by placing an inert final product as a catalyst to the healingprocess. This premature act certainly does not account for thephysiologic process of bone development and healing.

The physiologic process of bone healing can be broken down to threephases: (a) inflammation; (b) osteogenesis; and (c) remodeling.Inflammation is the first reaction to injury and a natural catalyst byproviding the chemotactic factors that will initiate the healingprocess. Osteogenesis is the next phase where osteoblasts respond andstart creating osteoid, the basic material of bone. Remodeling is thefinal phase in which osteoclasts and osteocytes then recreate thethree-dimensional architecture of bone.

In a normal tissue repair process, at the initial phase a fibrin clot ismade that provides a fibrous architecture for cells to adhere. This isthe cornerstone of all connective tissue healing. It is this fibrousarchitecture that allows for direct cell attachment and connectivitybetween cells. Ultimately, the goal is to stimulate cell proliferationand osteogenesis in the early healing phase and then allow forphysiologic remodeling to take place. Since the desired end product isliving tissue, the primary objective is to stimulate as much living boneas possible by enhancing the natural fiber network involved ininitiation and osteogenesis as well as angiogenesis.

Fibrous bone graft materials and bone graft implants formed from thesefibrous materials have previously been disclosed in U.S. PatentApplication Publication No. 2011/0144764 entitled “Bone Graft Material”,U.S. Patent Application Publication No. 2011/0144763 entitled “DynamicBioactive Bone Graft Material Having an Engineered Porosity”, and inU.S. Patent Application Publication No. 2011/0140316 entitled “DynamicBioactive Bone Graft Material and Methods for Handling”, all of whichare co-pending and co-owned by applicants, the contents of which areincorporated herein by reference. These bone graft implants attempt torecapitulate the normal physiologic healing process by presenting thefibrous structure of the fibrin clot. Since these bioactive implantsmade of fibers are both osteoconductive as well as osteostimulative, thefibrous network will further enhance and accelerate bone induction.Further, the free-flowing nature of the bioactive fibrous matrix orscaffold allows for natural initiation and stimulation of bone formationrather than placing a rigid template that may impede final formation aswith current graft materials. The fibers of the implants can also beengineered to provide a chemical reaction known to selectively stimulateosteoblast proliferation or other cellular phenotypes.

The present disclosure provides several embodiments of fibrous bonegraft implants formed of bioactive glass fibers similar to thosepreviously disclosed by applicants. The bundles of bioactive glassfibers are ultraporous, and include a combination of nano, micro, mesoand macro pores. The fibrous nature of the material allows the bioactiveglass fibers to be easily molded or shaped into clinically relevantshapes as needed for different surgical and anatomical applications,while maintaining the material's porosity. One manner of molding orshaping the scaffold is by placing the fibers into a mold tray, similarto the manner described in U.S. Patent Application Publication No.2011/0140316 entitled “Dynamic Bioactive Bone Graft Material and Methodsfor Handling”. The implant may comprise bioactive glass fibers alone, orwith additives as described above.

Another manner of shaping the implant is with the use of a jig. Due tothe fibrous and pliable nature of the base material, it is also possibleto add a biological fluid to the fibrous matrix and press into a formedshape with the fluid contained therein. Of course, it is understood thatthe fibrous material may just as easily be compressed in a mold. Liquidslike bone marrow aspirate, glue or other binding agents may be added tothe material prior to molding. In addition, a solvent exchange may beutilized and the shaped material can be allowed to dry or cure to form ahardened solid scaffold for implantation.

The implants may be provided in clinically relevant shapes. Simpleshapes like cylinders or rods, or a strip, may be convenient for easyimplantation. Alternatively, the implants may take the form of complexshapes to closely match the anatomy of the patient. For example, theimplants may be formed in the shape of a shell, such as for instance anacetabulum shell. In another example, the material may be formed as athin sheet or strip that is capable of being wrapped around the bonearea to be treated, such as a bone defect site, much like a wounddressing. In that instance, the sheet or strip of material would notnecessarily have to be inserted into the wound site, but rather coverthe wound site while still providing the same benefits and acting in thesame manner as the implants described herein.

The implants may be packaged in a clinically useful and friendly tray.The tray may be closed to control density and consequently dosage of theimplant. The dosage may be dictated by the clinical application. It isalso possible to use the tray as a mold, such that the shape of the traycreates a clinically relevant shaped implant. Another benefit of thetray is to allow fluids or liquids to be added to the implant. Suchfluids may include saline, bone marrow, bone marrow concentrate, stemcells, platelet-rich plasma, etc. The closed tray also avoidscontamination of the implant while it is in the operating room beforeimplantation, as it minimizes the need for clinical handling beforeimplantation, and is convenient for transport.

The fibers forming the engineered scaffold have a relatively smalldiameter, and in particular, a diameter in the range of about 500nanometers to about 50 microns, or a diameter in the range of about 0.1to about 100 microns. In one embodiment, the fiber diameter can be lessthan about 10 nanometers, and in another embodiment, the fiber diametercan be about 5 nanometers. In some embodiments, the fiber diameter canbe in the range of about 0.5 to about 30 microns. In other embodiments,the fiber diameter can fall within the range of between about 2 to about10 microns. In still another embodiment, the fiber diameter can fallwithin the range of between about 3 to about 4 microns.

The bioactive glass fibers may be manufactured having predeterminedcross-sectional diameters as desired. In one example, the bone graftimplant may be formed from a randomly oriented matrix of fibers ofuniform diameters. Further, the bioactive glass fibers may be formedhaving varying diameters and/or cross-sectional shapes, and may even bedrawn as hollow tubes. Additionally, the fibers may be meshed, woven,intertangled and the like for provision into a wide variety of shapes.

For example, a bioactive glass fiber implant can be manufactured suchthat each fiber is juxtaposed or out of alignment with the other fiberscould result in a randomly oriented fibrous matrix appearance due to thelarge amount of empty space created by the random relationship of theindividual glass fibers within the implant. Such a manufacture enablesan implant with an overall soft or pliable texture so as to permit thesurgeon to manually form the implant into any desired overall shape tomeet the surgical or anatomical requirements of a specific patient'ssurgical procedure. Such an implant also easily lends itself toincorporating additives randomly dispersed throughout the fibers, suchas those previously described and including bioactive glass granules,antimicrobial fibers, particulate medicines, trace elements or metalssuch as copper, which is a highly angiogenic metal, strontium,magnesium, zinc, etc. mineralogical calcium sources, and the like.Further, the bioactive glass fibers may also be coated with organicacids (such as formic acid, hyaluronic acid, or the like), mineralogicalcalcium sources (such as tricalcium phosphate, hydroxyapatite, calciumcarbonate, calcium hydroxide, calcium sulfate, or the like),antimicrobials, antivirals, vitamins, x-ray opacifiers, or other suchmaterials.

The implant may be engineered with fibers having varying resorptionrates. The resorption rate of a fiber is determined or controlled by,among other things, its material composition and by its diameter. Thematerial implant may result in a slow reacting vs. faster reactingproduct. Similarly, smaller diameter fibers can resorb faster thanlarger diameter fibers. Also, the overall porosity of the material canaffect resorption rate. Materials possessing a higher porosity meanthere is less material for cells to remove. Conversely, materialspossessing a lower porosity mean cells have to do more work, andresorption is slower. Accordingly, the implant may contain fibers thathave the appropriate material composition as well as diameter foroptimal performance. A combination of different fibers may be includedin the implant in order to achieve the desired result. For instance, theimplant may comprise a composite of two or more fibers of a differentmaterial, where the mean diameter of the fibers of each of the materialscould be the same or different.

Equally as important as the material composition and diameter is thepore size distribution of the open porosity and in particular thesurface area of the open porosity. The present bone graft implantsprovide not only an improved pore size distribution over other bonegraft implants, but a higher surface area for the open pores. The largersurface area of the open porosity of the present implants drives fasterresorption by body fluids, allowing the fluid better access to thepores.

In some embodiments, at least some or all of the engineered implant maybe coated with a glass, glass-ceramic, or ceramic coating. The coatingmay be solid or porous, and provide for better handling of the fibrousbioactive glass material. In one embodiment, the coating may be abioactive glass such as 45S5 or S53P4. In another embodiment, thecoating may be partially or fully fused such as by an application ofhigh heat to melt some of the fibrous material, creating a slightlyhardened or fully fused shell of material. For instance, this fusing orhardening would lead to a semi-soft crust, while the full sinteringwould lead to a hard crust around some or all of the implant.

The embodiments of the present disclosure are not limited, however, tofibers alone. In other embodiments, the bioactive glass fibers that formthe foundation of the implant may be substituted or supplemented withbioactive granules. These granules may be uniform or non-uniform indiameter, and may comprise a mixture of differently sized diameters ofgranules. In addition, the granules may be formed of the same type ofbioactive glass material, or a mixture of different materials selectedfrom the group of suitable materials previously mentioned. The granulesmay be solid or porous, and in some cases a mixture of both solid andporous granules may be used. Regardless, the engineered implantcomprising the granular foundation should still provide the desired poresize distribution, which includes a range of porosities that includesmacro, meso, micro and nano pores.

Like the fibers, at least some or all of the granules forming theengineered scaffold may be coated with a glass, glass-ceramic, orceramic coating. The coating may be solid or porous. In one embodiment,the coating may be a bioactive glass such as 45S5 or S53P4. In anotherembodiment, the coating may be partially or fully fused. This coatingcould be provided on individual granules, or it could envelope a clusteror group of granules. The coating may be partially fused or hardened, orfully fused to provide a semi-soft to fully hardened crust around someor all of the scaffold. Added surface features including fibers,granules, particulates, and the like can be included in the coating toprovide an exterior with bioactive anchorage points to attract cellularactivity and improve adhesion of the implant in situ.

In addition, some embodiments may include a mixture of both granularbioactive glass as the primary material with secondary bioactive glassfibers as the carrier material. In such cases, both the primary andsecondary materials are active. The fibrous carrier would be able toresorb quickly to create a chemically rich environment for inducing newcellular activity. Moreover, the fibrous material would serve as selectattachment or anchorage sites for bone forming cells.

In addition to providing a structurally sound implant formed of theappropriate materials and possessing the porosities and pore sizegradient for cell proliferation, the present bone graft materials andimplants may also provide cell signals. This can be accomplished by theincorporation of biological agents such as growth factors. These factorsmay be synthetic, recombinant, or allogenic, and can include, forexample, stem cells, deminerealized bone matrix (DBM), as well as otherknown cell signaling agents.

In some embodiments, the engineered implants may be also osteoconductiveand/or osteostimulatory. By varying the diameter and chemicalcomposition of the components used in the embodiments, the engineeredimplants may have differential activation (i.e., resorbability), whichmay facilitate advanced functions like drug delivery of such drugs asantibiotics, as an example. One manner of providing osteostimulativeproperties to the implant is to incorporate bone marrow into the fibrousmatrix. The incorporation of the marrow would produce anosteostimulative implant that accelerates cell proliferation.

In other embodiments, the engineered implant may also include traceelements or metals such as copper, zinc, strontium, magnesium, zinc,fluoride, mineralogical calcium sources, and the like. These traceelements provide selective benefits to the engineered structural andfunctioning scaffolds of the present disclosure. For example, theaddition of these trace elements like strontium may increase x-rayopacity, while the addition of copper provides particularly effectiveangiogenic characteristics to the scaffold. The materials may also becoated with organic acids (such as formic acid, hyaluronic acid, or thelike), mineralogical calcium sources (such as tricalcium phosphate,hydroxyapatite, calcium sulfate, calcium carbonate, calcium hydroxide,or the like), antimicrobials, antivirals, vitamins, x-ray opacifiers, orother such materials. These bone graft implants may also possessantimicrobial properties as well as allow for drug delivery. Forexample, sodium or silver may be added to provide antimicrobialfeatures. In one embodiment, a layer or coating of silver may beprovided around the engineered implant to provide an immediateantimicrobial benefit over an extensive surface area of the implant.Other suitable metals that could be added include gold, platinum,indium, rhodium, and palladium. These metals may be in the form ofnanoparticles that can resorb over time.

Additionally, biological agents may be added to the engineered implant.These biological agents may comprise bone morphogenic protein (BMP), apeptide, a bone growth factor such as platelet derived growth factor(PDGF), vascular endothelial growth factor (VEGF), insulin derivedgrowth factor (IDGF), a keratinocyte derived growth factor (KDGF), or afibroblast derived growth factor (FDGF), stem cells, bone marrow, andplatelet rich plasma (PRP), to name a few. Other medicines may beincorporated into the scaffold as well, such as in granule or fiberform.

In general, the present disclosure provides bone graft materials andimplants formed from these materials that are engineered with acombination of structural and functional features that act in synergy toallow the bone graft implant to support cell proliferation and newtissue growth over time. The implants provide the necessary porosity,pore size distribution and high surface area to allow propervascularization, optimized cell attachment, migration, proliferation,and differentiation. The implants are formed of synthetic materials thatare biocompatible and offer the requisite mechanical integrity tosupport continued cell proliferation throughout the healing process.These implants may comprise a fibrous or granular infrastructure ofporous material.

Embodiments of the present disclosure may be explained and illustratedwith reference to the drawings. It should be understood, however, thatthe drawings are not drawn to scale, and are not intended to representabsolute dimensions or relative size. Rather, the drawings help toillustrate the concepts described herein.

Turning now to the drawings, FIG. 1A shows an exemplary embodiment of animplant 10 of the present disclosure. The implant 10 may be formed offibrous bioactive glass material 20. Optionally, the implant 10 maycomprise one or more different glass materials to vary the compositionof the fibrous matrix. For instance, implant 10 of FIG. 1A comprises afirst bioactive glass fiber 20 as well as a bioactive fiber 24 that maycomprise another material. This material may be another bioactive glass,or it may be a glass, glass-ceramic, or ceramic material.

In some embodiments, the different fibers 20, 24 may be provided withthe same mean diameter, as illustrated in FIG. 1B. Alternatively, asshown in FIG. 1C, one of the fibers 24 may have a different diameterthan the other fiber 20. By varying the diameters of each of thematerials, this produces an implant that is selectively composed andstructured to have differential or staged resorption capacity.

The implant 10 of the present disclosure may have free-flowing fibersrandomly oriented within a matrix as illustrated in FIGS. 1A-1C. If sodesired, the fibers 20 may be partially or fully fused or sintered in amanner previously described, thus creating a semi-hard or fully hardenedfibrous matrix. FIG. 2 illustrates a fused fibrous implant 10 wherebythe fibers 20 appear to connect at intersections 22. Similar to theimplant of FIG. 1A, the fibrous matrix may comprise one or moredifferent glass materials to vary the composition of the implant. Inaddition, the diameters of each of the fibrous materials may also varyso as to produce an engineered implant that is selectively composed andstructured to have differential or staged resorption capacity.

Each of the individual fibers 20 may be coated with a coating 30, asshown in FIGS. 3 and 4. This coating 30 may comprise a bioactivematerial as previously disclosed, but could also be a differentbioactive glass material than the fibers 20. In one embodiment, thecoating may be a bioactive glass such as 45S5 or S53P4. In anotherembodiment, the coating may comprise a glass, glass-ceramic, or ceramiccoating. The coating 30 may be solid, or may be porous. For instance,the coating may have ports or vents that allow free migration of cellsand nutrients. These vents could be nano, micro, meso, or macro sizedopenings. A coating 30 over the individual fibers 20 may provide forbetter handling of the fibrous bioactive glass material.

In another embodiment, the coating may be hardened, such as shown inFIG. 4, over the individual fibers. As previously mentioned, thishardening can be achieved by applying very high heat to the coating andeffectively melting or fusing some or all of the material to create aprotective shell 30 around each of the fibers 20. These coated fiberswould then be formed into the fibrous matrix of the implant 10.

Rather than coating individual fibers, it is possible to coat the entirefibrous matrix as shown in FIG. 5A. The fibrous matrix may comprisefree-flowing, randomly oriented fibers 20 that can be encased in acoating or shell 30. This shell 30 may comprise a glass, glass-ceramic,or ceramic, and could be a bioactive glass such as 45S5 or S53P4. Theshell 30 may be porous, and provide for better handling of the fibrousbioactive glass material. These pores or vents 34 allow free migrationof cells and nutrients within the internal fibrous matrix, therebyimproving the healing process. As further shown in FIG. 5A, the shell 30may also include short wavy fiber segments 32 that serve as surfacefeatures to enhance anchorage of the implant 10 in situ. These shortwavy fiber segments 32 may be the fibers 20 extending out of the shell30, or it may be discrete short fiber segments 32 added to the shell 30.

In another embodiment, as shown in FIG. 5B, the shell 30 may be hardenedby passing the construct over very high heat for a limited duration oftime. The underlying fibrous matrix may also be partially or fully fusedin the same manner, as illustrated in FIG. 5C. In the case of anunsintered fibrous matrix such as shown in FIG. 5B, the interior of theconstruct could be relatively soft and conformable. The exterior of theconstruct would be a relatively hard crust or shell, however. Thehardness of the crust would necessarily depend on the temperature of theheat being applied and the duration of the application.

It is contemplated that in some embodiments where a glass,glass-ceramic, or ceramic coating is applied, either fibers or granules,or a combination of both, may be added to the coating. The fibers orgranules, which themselves may or may not be coated, would extend beyondthe outer surface of the scaffold, providing a surface feature thatenhances adhesion and creates a cell attachment surface. FIGS. 5A-5Cillustrate this concept.

As shown in FIGS. 5A-5C, the shell 30 may also include short wavy fibersegments 32 that serve as surface features to enhance anchorage of theimplant 10 in situ. These short wavy fiber segments 32 may be the fibers20 extending out of the shell 30, or it may be discrete short fibersegments 32 added to the shell 30. The shell 30 may also be porous orvented. These pores or vents 34 allow free migration of cells andnutrients within the internal fibrous matrix, thereby improving thehealing process.

In some embodiments, the implant 10 may be formed of a fibrous matrix aspreviously described, in combination with granules of bioactivematerial. In this instance, the fibrous matrix may serve as the primarycarrier material for the granules. The granules may comprise glass,glass-ceramic, or ceramic, and may be formed of a bioactive glassmaterial similar to the fibers 20 or a different bioactive glassmaterial.

FIGS. 6A-6C show various embodiments of combinations of fibers plusgranule or fiber clusters. FIG. 6A shows an engineered implant 10 thatmay comprise fibers 20 in combination with fibrous clusters 40 formed byagitating the fibers 20 to create a cluster shape. The materials of thefibers 20 and the clusters 40 may be the same, or of varying bioactiveglass materials.

The presence of granular matter may be employed to modify or control theresorption rate and resorption profile of the implant 10 as well asprovide mechanical strength and compression resistance. The granule maybe a bioactive glass, calcium sulfate, calcium phosphate, calciumcarbonate, calcium hydroxide, or hydroxyapatite. The granule may besolid, or it may be porous. These granules may serves as anchors forcell attachment, spacers between fibers to control distribution anddosage, or carry biological agents to provide antimicrobial propertiesor osteostimulative agents.

As shown in FIG. 6B, the granule 42 may be fused or sintered. The fibersand/or granules may further include a glass, glass-ceramic, or ceramiccoating, as illustrated in FIG. 6C. The coating 30 may be porous, andprovide for better handling of the fibrous bioactive glass material. Inone embodiment, the coating may be a bioactive glass such as 45S5 orS53P4. In another embodiment, the coating may be hardened as describedabove. The underlying matrix may be sintered or not, as previouslydescribed. The coating 30 may be selectively placed over the fibersonly, the granules only, or on both or some portion of each.

FIG. 6C illustrates an embodiment where the coating 30 resides as ashell over the entire fibrous matrix with granules 44 that areindividually coated as well. As further shown, the shell 30 may alsoinclude short wavy fiber segments 32 as well as granules 52 that serveas surface features to enhance anchorage of the implant 10 in situ.These short wavy fiber segments 32 may be the fibers 20 extending out ofthe shell 30, or they may be discrete short fiber segments 32 added tothe shell 30. Likewise, the granule 52 on the exterior of the shell 30may be the granule 44 of the matrix and extending from the shell, orthey may be discrete granules 52 added to the shell. The shell 30 mayalso be porous or vented. These pores or vents 34 allow free migrationof cells and nutrients within the internal fibrous matrix, therebyimproving the healing process.

The inclusion of bioactive glass granules can be accomplished usinggranules having a wide range of sizes or configurations to includeroughened surfaces, very large surface areas, and the like. For example,granules may be tailored to include interior lumens with perforations topermit exposure of the surface of the granule's interior. Such granuleswould be more quickly absorbed, allowing a tailored materialcharacterized by differential resorbability. The perforated or porousgranules could be characterized by uniform diameters or uniformperforation sizes, for example. The porosity provided by the granulesmay be viewed as a secondary range of porosity accorded the bone graftmaterial or the implant formed from the bone graft material. By varyingthe size, transverse diameter, surface texture, and configurations ofthe bioactive glass fibers and granules, if included, the manufacturerhas the ability to provide a bioactive glass bone graft material withselectively variable characteristics that can greatly affect thefunction of the implant 10 before and after it is implanted in apatient. The nano and macro sized pores provide superb fluid soak andhold capacity, which enhances the bioactivity and accordingly the repairprocess.

Accordingly, the engineered implant 10 can be selectively determined bycontrolling implant and manufacturing variables, such as bioactive glassfiber diameter, size, shape, and surface characteristics as well as theamount of bioactive glass granule content and structuralcharacteristics, and the inclusion of additional additives, such as, forexample tricalcium phosphate, hydroxyapatite, and the like. Byselectively controlling such manufacturing variables, it is possible toprovide an artificial bone graft material having selectable degrees ofcharacteristics such as porosity, bioabsorbability, tissue and/or cellpenetration, calcium bioavailability, flexibility, strength,compressibility and the like.

The same bioactive glass fibers 20 may be formed into clusters 120 withrelative ease. These clusters 120 can be achieved with a littlemechanical agitation of the bioactive glass fibrous material, aspreviously mentioned. The resultant fibrous clusters are extremelyporous and can easily wick up fluids or other nutrients. Hence, byproviding the bioactive glass material in the form of a porous, fibrouscluster, even greater clinical results and better handling can beachieved.

FIG. 7A represents an exemplary embodiment of a fibrous cluster 120. Asshown, the cluster 120 may be formed entirely of fibers. Optionally,these fibers may be individually coated with a coating 30 as describedabove. It is understood, of course, that an implant 10 may be formed offibrous clusters only, which implant 10 can be coated. In oneembodiment, short fibrous material may extend from the outside of theclusters to create anchorage sites in a manner previously described. Theindividual fibers may be coated with a glass, glass-ceramic, or ceramiccoating, similar to the one already described. Alternatively, the entirefibrous cluster may be coated with the glass, glass-ceramic, or ceramiccoating. The coating may be porous and may also be sintered.

In addition, these fibrous clusters 140 may be hardened by heating themat elevated temperatures, such as shown in FIG. 7B. The fused fibrousclusters 140 may optionally include hardened fibers on the exteriorsurface, which act as spikes 146 around the clusters 140. In some cases,the sintered fibrous clusters 160 may or may not present fibrousarchitecture, as shown in FIG. 7C. In this example, the porous clusters160 have fused such that the original fibrous architecture isundetected.

As mentioned, the presence of granular matter may be employed to modifyor control the resorption rate and resorption profile of the fiberclusters. FIG. 8 shows an embodiment of an engineered implant comprisingfibers 20 and granule 40 similar to those previously described. Thegranule may be solid, porous, or sintered, and may further be coatedwith a glass, glass-ceramic, or ceramic coating. As with previousembodiments, the implant may include exterior surface features such assoft, wavy short fibers or hardened fiber spikes.

FIG. 8 represents an exemplary embodiment in which the granules 40 arerandomly dispersed throughout the fibrous matrix 20. The entireconstruct may be encased in a shell 30, which may be porous or vented.These pores or vents 34 allow free migration of cells and nutrientswithin the internal fibrous matrix, thereby improving the healingprocess.

FIG. 9 represents an exemplary embodiment in which the granules 40 arediscreetly oriented in a layer surrounding the fibrous matrix 20.Similar to FIG. 8, the entire construct may be encased in a shell 30,which may be porous or vented. These pores or vents 34 allow freemigration of cells and nutrients within the internal fibrous matrix,thereby improving the healing process. Additionally, the shell 30 mayalso include short wavy fiber segments 32 as well as granules 52 (notshown) that serve as surface features to enhance anchorage of theimplant 10 in situ. These short wavy fiber segments 32 may be the fibers20 extending out of the shell 30, or they may be discrete short fibersegments 32 added to the shell 30. It is understood, of course, that theorientation of the layers may be reversed such that the fibers 20 residein a layer around a matrix comprising the granules 40, if so desired.

The formed and shaped bioactive glass implants of the presentdisclosure, either with or without sintering, share the similarattributes of a finite density material that has been dictated by itsprocessing and the fiber dimensions of the base material (e.g., diameterand length of the fibers) that resulted in the cluster formation. Theultra-porous clusters can possess micro, meso, and macro porosity in agradient throughout the cluster. Under a consistent manufacturingprocess, the formed clusters of bioactive glass can be used withvolumetric dosage to fill a bone defect. Any number of differently sizedclusters can be provided for various clinical applications.

In addition, it is also possible to provide a construct representing acomposite of bioactive glass materials not only in different shapes(i.e., fibers versus granules) but also different formulations. Forexample, in one embodiment, a bioactive glass material is provided as adissolved concentrated solution that may be incorporated into the fibersor granules of the primary bioactive glass component of the implant. Inone case, a borate-based bioactive glass may be dissolved, andintroduced into the pores of a silica-based borate bioactive glassmaterial. The dissolved borate-based material acts as a medicinal agent,releasing a burst of dissolution product upon implantation withouthaving to wait for the underlying, primary silica-based bioactive glassmaterial to dissolve. That is, the dissolved bioactive glass material iscarried within the porous matrix formed by the primary bioactive glassmaterial and delivered via this porous matrix. This provides the userwith the benefits of a second bioactive glass component without havingto alter the implant of the carrier, or primary bioactive glassmaterial. In addition, such an example would allow the use of morechemically stable glasses without the loss of the benefit of fasterreacting or resorbing glasses. The dissolution product also serves tohelp upregulate biologically active agents such as BMP, for instance.

One of the benefits of providing an ultra-porous bioactive glassmaterial in cluster or granular form is that handling of the materialcan be improved. In one manner of handling the granular material, thegranules may be packaged in a syringe with a carrier, and injected intothe bone defect with ease. Another benefit is the additional structuraleffect of having a plurality of clusters closely packed together,forming additional macrostructures to the overall scaffold of material.Like a sieve, the openings between individual clusters can be beneficialsuch as when a filter is desired for various nutrients in blood or bonemarrow to concentrate certain desired nutrients at the implant location.

While granular matter may be employed to modify or control theresorption rate and resorption profile of the fiber clusters, it islikewise also possible to provide an engineered implant having nofibers. FIG. 10 shows an implant 120 comprising fibrous clusters 40 andgranules 60. In some embodiments, the granules 60 may reside within thefibrous clusters 40. The granules 60 may be solid, porous, or sintered,and may further be coated with a glass, glass-ceramic, or ceramiccoating. The granules 60 provide the base for bone-forming cells, and inthis example, the granule-based matrix serves as the carrier materialfor the fibrous clusters 40. Although not shown, it is understood thatthe implant 120 may optionally comprise fibers or other additives aspreviously mentioned.

Another implant useful for clinical applications is a kneadable,conformable, or otherwise moldable formulation or putty. Putty implantsare desirable because the putty can be applied directly to the injurysite by either injection or by plastering. Putty implants are also easyto handle and moldable, allowing the clinician the flexibility to formthe material easily and quickly into any desired shape. In addition, theputty possesses the attributes of malleability, smearability, andinjectability.

Accordingly, the bioactive glass material may be mixed with a carriermaterial for better clinical handling, such as to make a putty or foamimplant. A pliable implant in the form of a putty may be provided bymixing the bioactive glass material with a flowable or carrier. A foamimplant may be provided by embedding the bioactive glass material in aporous matrix such as collagen (either human or animal derived) orporous polymer matrix. One of the advantages of a foam implant is thatthe porous carrier can also act as a site for attaching cells and growthfactors, and may lead to a better managed healing.

The carrier material may be porous and may help contribute to healing.For example, the carrier material may have the appropriate porosity tocreate a capillary effect to bring in cells and/or nutrients to theimplantation site, similar to the benefits that the fibers provide. Thecarrier material may also possess the chemistry to create osmotic orswelling pressure to bring in nutrients to the site and resorb quicklyin the process. For instance, the carrier material may be a polyethyleneglycol (PEG) which has a high affinity to water.

In one embodiment, the putty may have a more fluid than kneadableconsistency to allow to be easily injected from a syringe or otherinjection system. This could be very useful in a minimally invasivesystem where you want as little disruption to the damaged site and tothe patient as possible. For instance, a treatment may involve simplyinjecting the flowable putty of material into the area of bone damageusing a syringe, cannula, injection needle, delivery screw, or othermedical delivery portal for dispersal of injectable materials. Thistreatment may be surgical or non-surgical.

The combination of the ultra-porous fibrous clusters formed of bioactiveglass, combined with porous bioactive glass granules and a carriermaterial, forms an improved putty implant over currently availableputties. As shown in FIG. 11, the putty 200 may comprise fibers 20 andfiber clusters 40 in a carrier material 80. In one embodiment, the puttyimplant 220 may comprise fibrous clusters 40 as previously mentioned,bioactive glass granules 60, and the carrier material 80, as shown inFIG. 12. The sintered fibrous clusters as well as the bioactive glassgranules may be porous, where each component may have a range orgradient of porosities throughout. The combination thus provides theputty with variable resorption rates. As mentioned above, these fiberand glass clusters may be engineered with variable porosities, allowingthe customization of the putty formulation. In some embodiments, theputty includes any combination of nanopores, macropores, mesopores, andmicropores.

In other embodiments, the collagen may be a fully or partially watersoluble form of collagen to allow the collagen to soften with theaddition of fluids. In still other embodiments, the collagen may be acombination of soluble and fibrous collagen. The collagen may be humanderived collagen, in some instances, or animal derived collagen.

The use of sintered fiber clusters may be advantageous in someinstances, because the sintering provides relative hardness to theclusters, thereby rendering the sintered clusters mechanical stronger.Their combination with the glass granules further enhances thestructural integrity, mechanical strength, and durability of theimplant. Because larger sized granules or clusters will tend to havelonger resorption time, in previous cases the user had to sacrificestrength for speed. However, as applicants have discovered, it ispossible to provide larger sized granules or clusters to achievemechanical strength, without significantly sacrificing the speed ofresorption. To this end, ultra-porous clusters may be utilized. Ratherthan using solid spheres or granules, ultra-porous clusters that havethe integrity that overall larger sized granules provide, along with theporosity that allows for speed in resorption, can be used. Theseultra-porous clusters will tend to absorb more nutrients, resorbquicker, and lead to much faster healing and remodeling of the defect.

As shown in the scanning electron micrographs of FIGS. 13 to 16, thefibrous matrix of the implant may take the form of a cluster, such asshown in FIG. 13, whereby the fibrous architecture of the implant isevident. This fibrous architecture provides the implant with a structurethat mimics the structure of a human fibrin clot. Granules may beincorporated into the fibrous matrix, and such granules may extend outof the exterior of the implant, as shown in FIG. 14.

FIG. 15 shows a fibrous granule having a partially hardened shell. Thisshell is also porous to allow cell and nutrient exchange. As shown ingreater detail in FIG. 16, individual fibers within the fibrous matrixof the granule are also porous.

In some embodiments, the fiber diameter may be in the range of aboutabout 0.1 to about 100 microns. In other embodiments, the diameter canbe the range of about 0.5 to about 30 microns. In still otherembodiments, the diameter can be less than about 10 microns. In oneembodiment, the fiber diameter can fall within the range of betweenabout 2 to about 10 microns.

In some embodiments, the fiber clusters may have a diameter in the rangeof about 0.75 to about 4.0 mm. In other embodiments, the fiber clustersmay have a diameter in the range of about 2.0 to 4.0 mm.

In some embodiments, the glass granules may have a diameter in the rangeof about 1 to 5 mm, or about 950 microns to about 3 mm, or about 850microns to about 3 mm. In other embodiments, the glass granules may havea diameter in the range of about 50 to 450 microns, or about 150 to 450microns.

The carrier material for the putty implant can be phospholipids,carboxylmethylcellulose (CMC), glycerin, polyethylene glycol (PEG),polylactic acid (PLA), polylactic-co-glycolic acid (PLGA), or othercopolymers of the same family. Other suitable materials may includehyaluronic acid, or sodium alginate, for instance. The carrier materialmay be either water-based or non-water based, and may be viscous.Another carrier material alternative is saline or bone marrow aspirate,to provide a stickiness to the implant. Additives such as thosedescribed above, such as for example, silver or another antimicrobialcomponent, may also be added to provide additional biologicalenhancements.

As previously mentioned, the fiber clusters may be sintered to providehard clusters. Of course, it is contemplated that a combination of bothsintered fiber clusters (hard clusters) and unsintered clusters (softclusters) may be used in one application simultaneously. Likewise thecombination of putty, foam, and clusters as described herein may be usedin a single application to create an even more sophisticated porositygradient and ultimately offer a better healing response. In some cases,solid porous clusters of the bioactive glass material may also beincorporated into the implant.

Additionally, these fibrous clusters may be encased or coated with aglass, glass-ceramic, or ceramic material. The coating material itselfmay be porous and comprise bioactive glass such as 45S5 or S53P4. Thus,a fibrous cluster may be further protected with a coating formed of thesame material as the fibers, or a different material. The advantage ofcoating these fibrous clusters is to provide better handling sincehighly porous materials tend to have low strength, are prone to breakageand can become entangled. The addition of a coating having the sameproperties as the underlying fibrous foundation would therefore create abead-like implant that offers yet another layer of protection as well asan additional porosity gradient. The coating may itself be sintered orunsintered, allowing the user with the flexibility of customizing theend product to a desired hardness or softness. The process of coating amatrix with a bioactive glass layer has been described in U.S. patentapplication Ser. No. 13/429,629 filed Mar. 26, 2012, now U.S. Pat. No.8,449,904, the content of which is incorporated herein by reference inits entirety.

It is contemplated that the putty could be formulated for injectabledelivery. For example, one manner in which to apply the putty wouldinclude a syringe containing the bioactive material that can be openedto suction into the syringe the necessary fluid to form the putty, whilethe same syringe can also be used to inject the as-formed putty implant.In other examples, a syringe with threaded attachments such as aremovable cap may be utilized for site-specific delivery.

In some embodiments, an engineered implant comprising fibers formed intoa cluster in the manner previously described, along with unsinteredfibers of a different material may be provided. The unsintered fiberswould serve as the carrier for the fibrous clusters. A putty implantcould be formed by adding saline or blood marrow aspirate, to provide astickiness to the implant. Thus the putty could include two differentbioactive glass materials.

In still another embodiment, the graft material may be provided in theform of a foam. For example, the addition of collagen to the base graftmaterial would produce a foam implant that could be shaped into strips,sheets, or cylindrical rolls. These strips, sheets, or rolls could thenbe easily cut, folded, or otherwise formed into the ultimate geometry ofthe implant. In addition, these sheets may serve as a wound dressing orwrap around the bone defect site for healing.

Although the engineered implants of the present disclosure is describedfor use in bone grafting, it is contemplated that the implants of thepresent disclosure may also be applied to soft tissue or cartilagerepair as well. Accordingly, the application of the implants providedherein may include many different medical uses, and especially where newconnective tissue formation is desired. One such clinical application isin the area of nucleus replacement, where the engineered scaffold couldbe inserted into the disc nucleus as part of a nucleus replacementtherapy. Another suitable clinical application is for large bone defectsor lesions, particularly with the addition of platelet rich plasma (PRP)to the scaffold implant. Even still, the scaffold may be applied as abone filler such as a replacement or substitute for bone cement in bonedefect repairs. A silane coating may be applied over the scaffold tomake it more suitable in that capacity.

Other embodiments of the invention will be apparent to those skilled inthe art from consideration of the specification and practice of thedisclosure provided herein. It is intended that the specification andexamples be considered as exemplary only, with a true scope and spiritof the disclosure being indicated by the following claims.

What is claimed is:
 1. A bone graft implant, comprising: a firstcomponent comprising a bioactive glass material in the form of aplurality of glass fibers; and a second component comprising a bioactiveglass material in the form of a bioactive glass crust at least partiallycovering the plurality of fibers; each of the first and secondcomponents having a different resorption capacity than the othercomponent; and a third component comprising a biological agent; whereinthe implant comprises a pore size distribution including porescharacterized by pore diameters ranging from about 100 nanometers toabout 1 millimeter.
 2. The implant of claim 1, wherein at least one ofthe first and second components is partially or fully sintered.
 3. Theimplant of claim 1, wherein at least one of the first and secondcomponents is porous.
 4. The implant of claim 1, wherein the firstcomponent further comprises bioactive glass granules.
 5. The implant ofclaim 4, wherein the bioactive glass crust extends over all of theplurality of fibers and granules.
 6. The implant of claim 1, wherein thebiological agent is selected from the group consisting of stem cells,demineralized bone matrix, bone marrow and platelet rich plasma.
 7. Theimplant of claim 1, wherein the biological agent is selected from thegroup consisting of bone morphogenic protein, a bone growth factor,vascular endothelial growth factor, insulin derived growth factor, akeratinocyte derived growth factor, and a fibroblast derived growthfactor.
 8. The implant of claim 1, wherein the bone growth factor isplatelet derived growth factor.
 9. The implant of claim 1, wherein thebioactive glass material is selected from the group consisting of solgel derived bioactive glass, melt derived bioactive glass, silica basedbioactive glass, silica free bioactive glass, phosphate based bioactiveglass, crystallized bioactive glass, and bioactive glass containingtrace elements.
 10. The implant of claim 9, wherein the bioactive glassmaterial comprises a silica free bioactive glass selected from the groupconsisting of borate based bioactive glass and phosphate based bioactiveglass.
 11. The implant of claim 1, further comprising a carriermaterial.
 12. The implant of claim 11, wherein the carrier materialcomprises human-derived collagen, animal-derived collagen,phospholipids, carboxylmethylcellulose (CMC), glycerin, polyethyleneglycol (PEG), polylactic acid (PLA), polylactic-co-glycolic acid (PLGA),or other copolymers of the same family.
 13. The implant of claim 11,wherein the carrier material comprises hyaluronic acid, sodium alginate,saline, or bone marrow aspirate.
 14. A bone graft implant, comprising: afirst component comprising a bioactive glass material in the form of aplurality of granules; and a second component comprising a bioactivematerial in the form of a bioactive glass crust at least partiallycovering the plurality of granules; each of the first and secondcomponents having a different resorption capacity than the othercomponent; and a third component comprising a biological agent; whereinthe implant comprises a pore size distribution including porescharacterized by pore diameters ranging from about 100 nanometers toabout 1 millimeter.
 15. The implant of claim 14, wherein the firstcomponent further comprises bioactive glass fibers.
 16. The implant ofclaim 14, wherein the coating comprises a bioactive glass orglass-ceramic.
 17. The implant of claim 14, wherein at least one of thefirst and second components is partially or fully sintered.
 18. Theimplant of claim 14, wherein at least one of the first and secondcomponents is porous.
 19. The implant of claim 14, wherein each of thegranules comprises a further coating comprising bioactive glass.
 20. Theimplant of claim 14, wherein the biological agent is selected from thegroup consisting of stem cells, demineralized bone matrix, bone marrowand platelet rich plasma.
 21. The implant of claim 14, wherein thebiological agent is selected from the group consisting of bonemorphogenic protein, a bone growth factor, vascular endothelial growthfactor, insulin derived growth factor, a keratinocyte derived growthfactor, and a fibroblast derived growth factor.
 22. The implant of claim21, wherein the bone growth factor is platelet derived growth factor.23. The implant of claim 14, wherein the bioactive glass materialcomprises sol gel derived bioactive glass, melt derived bioactive glass,silica based bioactive glass, silica free bioactive glass, or phosphatebased bioactive glass, partially crystallized bioactive glass, fullycrystallized bioactive glass, or bioactive glass containing traceelements.
 24. The implant of claim 23, wherein the bioactive glassmaterial comprises a silica free bioactive glass selected from the groupconsisting of borate based bioactive glass and phosphate based bioactiveglass.
 25. The implant of claim 14, further comprising a carriermaterial.
 26. The implant of claim 25, wherein the carrier materialcomprises human-derived collagen, animal-derived collagen,phospholipids, carboxylmethylcellulose (CMC), glycerin, polyethyleneglycol (PEG), polylactic acid (PLA), polylactic-co-glycolic acid (PLGA),or other copolymers of the same family.
 27. The implant of claim 25,wherein the carrier material comprises hyaluronic acid, sodium alginate,saline, or bone marrow aspirate.